Hemostatic Dysfunction in Paraproteinemias and Amyloidosis

ABSTRACT

Thrombotic and hemorrhagic complications frequently have been observed in patients with monoclonal gammopathy, Waldenström macroglobulinemia, amyloidosis, multiple myeloma (MM), and myeloma. Chemotherapy in combination with the use of antiangiogenic agents can further enhance the risk of cardiovascular complications. A malignancy-associated thrombophilic state (in particular, cytokine-induced high levels of factor VIII and von Willebrand factor) can also explain the high rate of thrombosis reported in these patients. Impaired fibrinolysis and a transient downregulation of the protein C system are recently discovered pathogenetic mechanisms. At diagnosis, when the highest VTE risk is present, baseline coagulation tests such activated protein C resistance may be helpful to identify patients who can benefit the most from anticoagulation; with the emerging evidence of a positive effect on survival of low molecular weight heparin, prospective trials are needed in this group of diseases.

KEYWORDS

Myeloma - paraproteinemia - amyloidosis - bleeding diathesis - thrombosis

REFERENCES

• 1 Sallah S, Husain A, Wan J, Vos P, Nguyen N P. The risk of venous thromboembolic disease in patients with monoclonal gammopathy of undetermined significance.  Ann Oncol. 2004;  15(10) 1490-1494
• 2 Srkalovic G, Cameron M G, Rybicki L et al.. Monoclonal gammopathy of undetermined significance and multiple myeloma are associated with an increased incidence of venothromboembolic disease.  Cancer. 2004;  101(3) 558-566
• 3 Barlogie B, Desikan R, Eddlemon P et al.. Extended survival in advanced and refractory multiple myeloma after single-agent thalidomide: identification of prognostic factors in a phase 2 study of 169 patients.  Blood. 2001;  98(2) 492-494
• 4 Weber D M, Chen C, Niesvizky R et al.. Lenalidomide plus high-dose dexamethasone provides improved overall survival compared to high-dose dexamethasone alone for relapsed or refractory multiple myeloma (MM): Results of a North American phase III study (MM-009).  J Clin Oncol. 2006;  24(18S) , 7521 (abst)
• 5 Dimopoulos M A, Spencer A, Attal M et al.. Study of lenalidomide plus dexamethasone versus dexamethasone alone in relapsed or refractory multiple myeloma (MM): results of a phase 3 study (MM-010).  Blood. 2005;  106 6 (abst)
• 6 Rajkumar S V, Blood E, Vesole D, Fonseca R, Greipp P R. for the Eastern Cooperative Oncology Group . Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical trial coordinated by the Eastern Cooperative Oncology Group.  J Clin Oncol. 2006;  24(3) 431-436
• 7 Osman K, Comenzo R, Rajkumar S V. Deep venous thrombosis and thalidomide therapy for multiple myeloma.  N Engl J Med. 2001;  344(25) 1951-1952
• 8 Singhal S, Mehta J, Desikan R et al.. Antitumor activity of thalidomide in refractory multiple myeloma.  N Engl J Med. 1999;  341(21) 1565-1571
• 9 Tosi P, Zamagni E, Cellini C et al.. Salvage therapy with thalidomide in patients with advanced relapsed/refractory multiple myeloma.  Haematologica. 2002;  87(4) 408-414
• 10 Kumar S, Gertz M A, Dispenzieri A et al.. Response rate, durability of response, and survival after thalidomide therapy for relapsed multiple myeloma.  Mayo Clin Proc. 2003;  78(1) 34-39
• 11 Anagnostopoulos A, Weber D, Rankin K, Delasalle K, Alexanian R. Thalidomide and dexamethasone for resistant multiple myeloma.  Br J Haematol. 2003;  121(5) 768-771
• 12 Cavo M, Zamagni E, Tosi P et al.. First-line therapy with thalidomide and dexamethasone in preparation for autologous stem cell transplantation for multiple myeloma.  Haematologica. 2004;  89(7) 826-831
• 13 Zangari M, Anaissie E, Barlogie B et al.. Increased risk of deep-vein thrombosis in patients with multiple myeloma receiving thalidomide and chemotherapy.  Blood. 2001;  98(5) 1614-1615
• 14 Zangari M, Siegel E, Barlogie B et al.. Thrombogenic activity of doxorubicin in myeloma patients receiving thalidomide: implications for therapy.  Blood. 2002;  100(4) 1168-1171
• 15 Biemond B J, Havik S R, Meijers J CM et al.. Strong thrombogenic activity of the combined administration of thalidomide and doxorubicin in experimental thrombosis in the rabbit.  Blood. 2003;  102(11) , 554 (abst 2036)
• 16 Zangari M, Barlogie B, Thertulien R et al.. Thalidomide and deep vein thrombosis in multiple myeloma: risk factors and effect on survival.  Clin Lymphoma. 2003;  4(1) 32-35
• 17 Cavenagh J D, Oakervee H. for the UK Myeloma Forum and the BCSH Haematology/Oncology Task Forces. . Thalidomide in multiple myeloma: current status and future prospects.  Br J Haematol. 2003;  120(1) 18-26
• 18 Richardson P G, Schlossman R L, Weller E et al.. Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma.  Blood. 2002;  100(9) 3063-3067
• 19 Richardson P G, Blood E, Mitsiades C S et al.. A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma.  Blood. 2006;  108 3458-3464
• 20 Zangari M, Elice F, Tricot G. Immunomodulatory drugs in multiple myeloma.  Expert Opin Investig Drugs. 2005;  14(11) 1411-1418
• 21 Zonder J A, Barlogie B, Durie B G et al.. Thrombotic complications in patients with newly diagnosed multiple myeloma treated with lenalidomide and dexamethasone: benefit of aspirin prophylaxis.  Blood. 2006;  108(1) 403
• 22 Rajkumar S V, Hayman S R, Lacy M Q et al.. Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma.  Blood. 2005;  106(13) 4050-4053
• 23 Srkalovic G, Cameron M G, Deitcher S R, Kattke-Marchant K, Hussein M A. Incidence and risk factors of venous thromboembolism (VTD) in patients with amyloidosis.  Int Semin Surg Oncol. 2005;  2 17
• 24 Halligan C S, Lacy M Q, Vincent Rajkumar S et al.. Natural history of thromboembolism in AL amyloidosis.  Amyloid. 2006;  13(1) 31-36
• 25 Sorensen H T, Mellemkjaer L, Olsen J H, Baron J A. Prognosis of cancers associated with venous thromboembolism.  N Engl J Med. 2000;  343(25) 1846-1850
• 26 Zacharski L R, Henderson W G, Rickles F R et al.. Effect of warfarin anticoagulation on survival in carcinoma of the lung, colon, head and neck, and prostate. Final report of VA Cooperative Study #75.  Cancer. 1984;  53(10) 2046-2052
• 27 Barlogie B, Tricot G, Anaissie E et al.. Thalidomide and hematopoietic-cell transplantation for multiple myeloma.  N Engl J Med. 2006;  354(10) 1021-1031
• 28 Zangari M, Barlogie B, Cavallo F et al.. Effect on survival of treatment associated venous thromboembolism in newly diagnosed multiple myeloma patients.  Blood Coagul Fibrinolysis. 2006;  , In press
• 29 O'Kane M J, Wisdom G B, Desai Z R, Archbold G P. Inhibition of fibrin monomer polymerisation by myeloma immunoglobulin.  J Clin Pathol. 1994;  47(3) 266-268
• 30 Gabriel D A, Smith L A, Folds J D, Davis L, Cancelosi S E. The influence of immunoglobulin (IgG) on the assembly of fibrin gels.  J Lab Clin Med. 1983;  101(4) 545-552
• 31 Carr Jr M E, Zekert S L. Abnormal clot retraction, altered fibrin structure, and normal platelet function in multiple myeloma.  Am J Physiol. 1994;  266(3 Pt 2) H1195-H1201
• 32 Carr Jr M E, Dent R M, Carr S L. Abnormal fibrin structure and inhibition of fibrinolysis in patients with multiple myeloma.  J Lab Clin Med. 1996;  128(1) 83-88
• 33 Yagci M, Sucak G T, Haznedar R. Fibrinolytic activity in multiple myeloma.  Am J Hematol. 2003;  74(4) 231-237
• 34 van Marion A M, Auwerda J J, Minnema M C et al.. Hypofibrinolysis during induction treatment of multiple myeloma may increase the risk of venous thrombosis.  Thromb Haemost. 2005;  94(6) 1341-1343
• 35 Duhren U, Paar D, Kolbel C et al.. Lupus anticoagulant associated syndrome in benign and malignant systemic disease-analysis of ten observations.  Klin Wochenschr. 1987;  65(18) 852-859
• 36 Bellotti V, Gambo G, Merlini G et al.. Study of three patients with monoclonal gammopathies and ‘lupus-like' anticoagulants.  Br J Haematol. 1989;  73(2) 221-227
• 37 Takamiya O, Machida S, Okuda M et al.. A non-immunological phospholipid-dependent coagulation inhibitor associated with IgG lambda-type multiple myeloma.  Am J Hematol. 2004;  75(1) 34-39
• 38 Tricot G. New insights into role of microenvironment in multiple myeloma.  Lancet. 2000;  355(9200) 248-250
• 39 Anderson K. Advances in the biology of multiple myeloma: therapeutic applications.  Semin Oncol. 1999;  26(5 suppl 13) 10-22
• 40 Yasui H, Hideshima T, Richardson P G et al.. Novel therapeutic strategies targeting growth factor signaling cascades in multiple myeloma.  Br J Haematol. 2006;  132(4) 385-397
• 41 Barille S, Bataille R, Amiot M. The role of interleukin-6 and interleukin-6/interleukin-6 receptor-alpha complex in the pathogenesis of multiple myeloma.  Eur Cytokine Netw. 2000;  11(4) 546-551
• 42 Mechtcheriakova D, Wlachos A, Holzmuller H et al.. Vascular endothelial cell growth factor-induced tissue factor expression in endothelial cells is mediated by EGR-1.  Blood. 1999;  93 3811-3823
• 43 Esmon C T. Possible involvement of cytokines in diffuse intravascular coagulation and thrombosis.  Baillieres Best Pract Res Clin Haematol. 1999;  12(3) 343-359
• 44 Amrani D L. Regulation of fibrinogen biosynthesis: glucocorticoid and interleukin-6 control.  Blood Coagul Fibrinolysis. 1990;  1(4-5) 443-446
• 45 Stirling D, Hannant W A, Ludlam C A. Transcriptional activation of the factor VIII gene in liver cell lines by interleukin-6.  Thromb Haemost. 1998;  79(1) 74-78
• 46 Minnema M C, Fijnheer R, De Groot P G, Lokhorst H M. Extremely high levels of von Willebrand factor antigen and of procoagulant factor VIII found in multiple myeloma patients are associated with activity status but not with thalidomide treatment.  J Thromb Haemost. 2003;  1(3) 445-449
• 47 Green D, Maliekel K, Sushko E, Akhtar R, Soff G A. Activated-protein-C resistance in cancer patients.  Haemostasis. 1997;  27(3) 112-118
• 48 Haim N, Lanir N, Hoffman R, Haim A, Tsalik M, Brenner B. Acquired activated protein C resistance is common in cancer patients and is associated with venous thromboembolism.  Am J Med. 2001;  110(2) 91-96
• 49 Zangari M, Saghafifar F, Anaissie E et al.. Activated protein C resistance in the absence of factor V Leiden mutation is a common finding in multiple myeloma and is associated with an increased risk of thrombotic complications.  Blood Coagul Fibrinolysis. 2002;  13(3) 187-192
• 50 Elice F, Fink L, Tricot G, Barlogie B, Zangari M. Acquired resistance to activated protein C (aAPCR) in multiple myeloma is a transitory abnormality associated with an increased risk of venous thromboembolism.  Br J Haematol. 2006;  134(4) 399-405
• 51 Hugo J Z, Jeanet D M. Acquired activated protein C resistance and thrombosis in multiple myeloma patients.  Thromb J. 2006;  4 11
• 52 Esmon C T. The impact of the inflammatory response on coagulation.  Thromb Res. 2004;  114(5-6) 321-327
• 53 Deitcher S R, Erban J K, Limentani S A. Acquired free protein S deficiency associated with multiple myeloma: a case report.  Am J Hematol. 1996;  51(4) 319-323
• 54 Otterson G A, Monahan B P, Harold N et al.. Clinical significance of the FV: Q506 mutation in unselected oncology patients.  Am J Med. 1996;  101(4) 406-412
• 55 Santos A B, Llamas P, Roman A et al.. Evaluation of thrombophilic states in myeloma patients receiving thalidomide: a reasonable doubt.  Br J Haematol. 2003;  122(1) 159-160
• 56 Rees D C, Cox M, Clegg J B. World distribution of factor V Leiden.  Lancet. 1995;  346(8983) 1133-1134
• 57 Koster T, Rosendaal F R, de Ronde H et al.. Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden Thrombophilia Study.  Lancet. 1993;  342(8886-8887) 1503-1506
• 58 Rosendaal F R, Koster T, Vandenbroucke J P, Reitsma P H. High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance).  Blood. 1995;  85(6) 1504-1508
• 59 Poort S R, Rosendaal F R, Reitsma P H, Bertina R M. A common genetic variation in the 3′-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis.  Blood. 1996;  88(10) 3698-3703
• 60 Corso A, Lorenzi A, Terulla V et al.. Modification of thrombomodulin plasma levels in refractory myeloma patients during treatment with thalidomide and dexamethasone.  Ann Hematol. 2004;  83(9) 588-591
• 61 Weber D, Ginsberg C, Walker P et al.. Correlation of thrombotic/embolic events (T/E) with features of hypercoagulability in previously untreated patients before and after treatment with thalidomide (T) or thalidomide-dexamethasone (TD).  Blood. 2002;  100(11) , (abst 787)
• 62 Ward C M, Yen T, Harvie R, Pavlakis N. Elevated levels of factor VIII and von Willebrand factor after thalidomide treatment for malignancy: relationship to thromboembolic events.  Hematol J. 2003;  4(suppl 1) 265 , (abst)
• 63 Auwerda J J, Sonneveld P, Leebeek F W. Temporary relief of symptomatic Von Willebrand disease by multiple myeloma.  J Thromb Haemost. 2005;  3(5) 1088-1089
• 64 Kyrle P A, Minar E, Hirschl M et al.. High plasma levels of factor VIII and the risk of recurrent venous thromboembolism.  N Engl J Med. 2000;  343(7) 457-462
• 65 Hussein M A. Thromboembolism risk reduction in multiple myeloma patients treated with immunomodulatory drug combinations.  Thromb Haemost. 2006;  95(6) 924-930
• 66 Sezer O, Jakob C, Eucker J et al.. Serum levels of the angiogenic cytokines basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) in multiple myeloma.  Eur J Haematol. 2001;  66(2) 83-88
• 67 Vacca A, Scavelli C, Montefusco V et al.. Thalidomide downregulates angiogenic genes in bone marrow endothelial cells of patients with active multiple myeloma.  J Clin Oncol. 2005;  23(23) 5334-5346
• 68 Weber D, Rankin K, Gavino M et al.. Thalidomide alone or with dexamethasone for previously untreated multiple myeloma.  J Clin Oncol. 2003;  21 16-19
• 69 Cunningham M S, White B, Hollywood D, O'Donnell J. Primary thromboprophylaxis for cancer patients with central venous catheters-a reappraisal of the evidence.  Br J Cancer. 2006;  94(2) 189-194
• 70 Perret-Guillaume C, Wahl D G. Low-dose warfarin in atrial fibrillation leads to more thromboembolic events without reducing major bleeding when compared to adjusted-dose-a meta-analysis.  Thromb Haemost. 2004;  91(2) 394-402
• 71 Zangari M, Barlogie B, Anaissie E et al.. Deep vein thrombosis in patients with multiple myeloma treated with thalidomide and chemotherapy: effects of prophylactic and therapeutic anticoagulation.  Br J Haematol. 2004;  126(5) 715-721
• 72 Lee A Y, Levine M N. Venous thromboembolism and cancer: risks and outcomes.  Circulation. 2003;  107(23 suppl 1) I17-I21
• 73 Minnema M C, Breitkreutz I, Auwerda J J et al.. Prevention of venous thromboembolism with low molecular-weight heparin in patients with multiple myeloma treated with thalidomide and chemotherapy.  Leukemia. 2004;  18(12) 2044-2046
• 74 Lee A Y, Levine M N, Baker R I et al.. Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) Investigators. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer.  N Engl J Med. 2003;  349(2) 146-153
• 75 Baz R, Li L, Kottke-Marchant K et al.. The role of aspirin in the prevention of thrombotic complications of thalidomide and anthracycline-based chemotherapy for multiple myeloma.  Mayo Clin Proc. 2005;  80(12) 1568-1574
• 76 Liebman H A, Benz E JJ, Shattil S J et al. Hemostatic defects associated with dysproteinemias. In: Hoffman R, et al Hematology: Basic Principles and Practice. 3rd ed. New York; Churchill Livingstone 2000: 1996-2000
• 77 Perkins H A, MacKenzie M R, Fudenberg H H. Hemostatic defects in dysproteinemias.  Blood. 1970;  35(5) 695-707
• 78 Kyle R A, Gertz M A. Primary systemic amyloidosis: clinical and laboratory features in 474 cases.  Semin Hematol. 1995;  32 45-59
• 79 Gamba G, Montani N, Anesi E et al.. Clotting alterations in primary systemic amyloidosis.  Haematologica. 2000;  85(3) 289-292
• 80 Saif M W, Allegra C J, Greenberg B. Bleeding diathesis in multiple myeloma.  J Hematother Stem Cell Res. 2001;  10(5) 657-660
• 81 Hoshino Y, Hatake K, Muroi K et al.. Bleeding tendency caused by the deposit of amyloid substance in the perivascular region.  Intern Med. 1993;  32(11) 879-881
• 82 Beardell F V, Varma M, Martinez J. Normalization of plasma factor X levels in amyloidosis after plasma exchange.  Am J Hematol. 1997;  54(1) 68-71
• 83 Gertz M A, Kyle R A. Hyperviscosity syndrome.  J Intensive Care Med. 1995;  10 128-141
• 84 Taher A, Abiad R, Uthman I. Coexistence of lupus anticoagulant and acquired haemophilia in a patient with monoclonal gammopathy of unknown significance.  Lupus. 2003;  12(11) 854-856
• 85 Mohri H, Noguchi T, Kodama F, Itoh A, Ohkubo T. Acquired von Willebrand disease due to inhibitor of human myeloma protein specific for von Willebrand factor.  Am J Clin Pathol. 1987;  87(5) 663-668
• 86 Loftus L S, Arnold W N. Acquired hemophilia in a patient with myeloma.  West J Med. 1994;  160(2) 173-176
• 87 Federici A B, Stabile F, Castaman G, Canciani M T, Mannucci P M. Treatment of acquired von Willebrand syndrome in patients with monoclonal gammopathy of uncertain significance: comparison of three different therapeutic approaches.  Blood. 1998;  92(8) 2707-27011
• 88 Hayashi T, Yagi H, Suzuki H et al.. Low-dosage intravenous immunoglobulin in the management of a patient with acquired von Willebrand syndrome associated with monoclonal gammopathy of undetermined significance.  Pathophysiol Haemost Thromb. 2002;  32(1) 33-39
• 89 Cohen I, Amir J, Ben-Shaul Y, Pick A, De Vries A. Plasma cell myeloma associated with an unusual myeloma protein causing impairment of fibrin aggregation and platelet function in a patient with multiple malignancy.  Am J Med. 1970;  48(6) 766-776
• 90 Penny R, Castaldi P A, Whitsed H M. Inflammation and haemostasis in paraproteinaemias.  Br J Haematol. 1971;  20(1) 35-44
• 91 Shinagawa A, Kojima H, Berndt M C et al.. Characterization of a myeloma patient with a life-threatening hemorrhagic diathesis: presence of a lambda dimer protein inhibiting shear-induced platelet aggregation by binding to the A1 domain of von Willebrand factor.  Thromb Haemost. 2005;  93(5) 889-896
• 92 Chapman G S, George C B, Danley D L. Heparinlike anticoagulant associated with plasma cell myeloma.  Am J Clin Pathol. 1985;  83 764-766
• 93 Kaufman P A, Gockerman J P, Greenberg C S. Production of a novel anticoagulant by neoplastic plasma cells: report of a case and review of the literature.  Am J Med. 1989;  86(5) 612-616
• 94 Liebman H, Chinowsky M, Valdin J, Kenoyer G, Feinstein D. Increased fibrinolysis and amyloidosis.  Arch Intern Med. 1983;  143(4) 678-682
• 95 Liebman H A, Carfagno M K, Weitz I C et al.. Excessive fibrinolysis in amyloidosis associated with elevated plasma single-chain urokinase.  Am J Clin Pathol. 1992;  98(5) 534-541
• 96 Sane D C, Pizzo S V, Greenberg C S. Elevated urokinase-type plasminogen activator level and bleeding in amyloidosis: case report and literature review.  Am J Hematol. 1989;  31(1) 53-57
• 97 Brody J I, Haidar M E, Rossman R E. A hemorrhagic syndrome in Waldenström's macroglobulinemia secondary to immunoadsorption of factor VIII. Recovery after splenectomy.  N Engl J Med. 1979;  300(8) 408-410
• 98 Greipp P R, Kyle R A, Bowie E J. Factor-X deficiency in amyloidosis: a critical review.  Am J Hematol. 1981;  11(4) 443-450
• 99 Furie B, Greene E, Furie B C. Syndrome of acquired factor X deficiency and systemic amyloidosis in vivo studies of the metabolic fate of factor X.  N Engl J Med. 1977;  297(2) 81-85
• 100 Furie B, Voo L, McAdam K P, Furie B C. Mechanism of factor X deficiency in systemic amyloidosis.  N Engl J Med. 1981;  304(14) 827-830
• 101 Galbraith P A, Sharma N, Parker W L, Kilgour J M. Acquired factor X deficiency. Altered plasma antithrombin activity and association with amyloidosis.  JAMA. 1974;  230(12) 1658-1660
• 102 Greipp P R, Kyle R A, Bowie E J. Factor X deficiency in primary amyloidosis: resolution after splenectomy.  N Engl J Med. 1979;  301(19) 1050-1051
• 103 Rosenstein E D, Itzkowitz S H, Penziner A S, Cohen J I, Mornaghi R A. Resolution of factor X deficiency in primary amyloidosis following splenectomy.  Arch Intern Med. 1983;  143(3) 597-599
• 104 Gertz M A, Fonseca R, Rajkumar S V. Waldenström's macroglobulinemia.  Oncologist. 2000;  5(1) 63-67
• 105 Weber D, Albitar M, Delasalle K et al.. Correlation of peripheral blood plasma levels of angiogenesis factors with treatment of thalidomide (T) or thalidomide - dexamethasone (TD) in previously untreated patients with multiple myeloma (MM).  Blood. 2002;  100(11) 808-809 , (abst 3193)
• 106 Neben K, Moehler T, Kraemer A et al.. Response to thalidomide in progressive multiple myeloma is not mediated by inhibition of angiogenic cytokine secretion.  Br J Haematol. 2001;  115(3) 605-608
• 107 Bertolini F, Mingrone W, Alietti A et al.. Thalidomide in multiple myeloma, myelodysplastic syndromes and histiocytosis. Analysis of clinical results and of surrogate angiogenesis markers.  Ann Oncol. 2001;  12(7) 987-990
• 108 Dmoszynska A, Bojarska-Junak A, Domanski D et al.. Production of proangiogenic cytokines during thalidomide treatment of multiple myeloma.  Leuk Lymphoma. 2002;  43(2) 401-406
• 109 Hassoun H, Reich L, Klimek V M et al.. Doxorubicin and dexamethasone followed by thalidomide and dexamethasone is an effective well tolerated initial therapy for multiple myeloma.  Br J Haematol. 2006;  132(2) 155-161
• 110 Palumbo A, Betrola A, Falco P et al.. Efficacy of low-dose thalidomide and dexamethasone as first salvage regimen in multiple myeloma.  Hematol J. 2004;  5(4) 318-324
• 111 Facon T, Mary J Y, Hulin C et al.. Major superiority of melphalan-prednisone (MP) + thalidomide (THAL) over MP and autologous stem cell transplantation in the treatment of newly diagnosed elderly patients with multiple myeloma.  Blood. 2005;  106 230 , (abst 780)
• 112 Palumbo A, Rus C, Zeldis J B, Rodeghiero F, Boccadoro M. Italian Multiple Myeloma Network, Gimema. Enoxaparin or aspirin for the prevention of recurrent thromboembolism in newly diagnosed myeloma patients treated with melphalan and prednisone plus thalidomide or lenalidomide.  J Thromb Haemost. 2006;  4(8) 1842-1845
• 113 Zervas K, Dimopoulos M A, Hatzicharissi E et al.. Greek Myeloma Study Group. Primary treatment of multiple myeloma with thalidomide, vincristine, liposomal doxorubicin and dexamethasone (T-VAD doxil): a phase II multicenter study.  Ann Oncol. 2004;  15(1) 134-138
• 114 Chanan-Khan A A, Miller K C, McCarthy P et al.. VAD-t (vincristine, adriamycin, dexamethasone and low-dose thalidomide) is an effective initial therapy with high response rates for patients with treatment naive multiple myeloma (MM).  Blood. 2004;  104 943-944 , (abst 3463)